The capacity of B lymphocytes to self-present peptides from antibody variable (V) regions in the context of class II MHC is at the root of an important regulatory paradox: how is antigen-specific T cell help delivered to B cells in the face of potential unregulated help delivered via "receptor presentations"? We proposed that this problem is averted under physiological circumstances by B cells that induce tolerance in T cells to self-presented V region peptides. During the previous funding period, the applicant has found that activated B cells, in contrast to resting B cells, proficiently display endogenous V region sequences in class II MHC. They also present de novo V region epitopes generated by somatic mutagenesis. We have also obtained evidence that in autoimmune-prone mice, T cells directed to somatically mutated Ig V region peptides may be providing an important avenue of help to recruit autoreactive B lymphocytes in systemic lupus erythematosus (SLE). Collectively, these findings suggest the importance of understanding how somatically-generated antibody diversity in activated B cells is perceived and handled by an immune system that must otherwise provide antigen-specific and MHC-restricted help to B cells during the course of physiological immunity. This is a major objective of this proposal. We will test the hypothesis that tolerance is specifically attained to somatic mutational diversity, either in the T cell repertoire or in the B cell repertoire. In situ studies will be performed to reveal cognate interactions between B and T lymphocytes that might be responsible for tolerance. The possibility that immunoregulation is achieved by a segregation mechanism rather than via tolerance will also be considered. The results obtained from this work could significantly advance our comprehension of important regulatory events that confer immunity without autoimmunity. And they will provide a roadmap for the design and delivery of therapeutic monoclonal antibodies that are both functional and nonimmunogenic.